The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's and Parkinson's disease. An exciting recent development is the elucidation of a pattern of DNA damage in the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity, vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be explained, at least in part, by oxidative DMA damage to vulnerable gene promoters provides a novel conceptual framework for understanding how the brain ages. Furthermore, we have begun to define the mechanism by which damaged genes are silenced by obtaining evidence for the involvement of a nuclear protein complex that contains the transcriptional co-repressor NCOR1, the human ortholog of the yeast ongevity gene SIR2 (Sirt1), and the DNA repair enzyme hOGG1. Our preliminary studies also suggest that this age-related process may be accelerated in Alzheimer's disease, and may predispose to aggregation of amyloid beta-protein (Abeta). These findings provide the basis for our hypothesis that DNA damage contributes to reduced expression of important neuronal genes in the aging brain, and that this process may underlie cognitive decline and vulnerability to neurodegeneration. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in the normal aging human brain. The mechanisms of selective DNA damage and gene silencing in the aging brain will be investigated, and the role of the newly defined DNA damage silencing complex involving Sirt1 (Project 3) will be defined. Transgenic mice that oyerexpress DNA repair enzymes will be generated to determine whether DNA damage contributes to age-related cognitive decline. These mice will also be mated with APPsw and Ck-p25 transgenic mice generated in Project 2 to determine the role of age-related DNA damage in the pathology of Alzheimer's disease. These studies may provide new insights into brain aging, with potentially significant therapeutic implications.